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首页> 美国卫生研究院文献>Journal of Biomolecular Techniques : JBT >Pathogenic Orphan Transduction Created by a Non-reference LINE-1 Retrotransposon
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Pathogenic Orphan Transduction Created by a Non-reference LINE-1 Retrotransposon

机译：非参考LINE-1反转录转座子产生的致病性孤儿转导。

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Long INterspersed Element-1 (LINE-1) retrotransposons comprise 17% of the human genome, and move by a potentially mutagenic “copy and paste” mechanism via an RNA intermediate. Recently, the retrotransposition-mediated insertion of a new transcript was described as a novel cause of genetic disease, Duchenne muscular dystrophy, in a Japanese male. The inserted sequence was presumed to derive from a single-copy, non-coding RNA transcribed from chr. 11q22.3 that retrotransposed into the dystrophin gene on chr. X. Here, we demonstrate that a non-reference full-length LINE-1 (termed LRE4) is situated in the proband and maternal genome at chromosome 11q22.3, directly upstream of the sequence, whose copy was inserted into the dystrophin gene. LRE4 is highly active in a cell culture assay. LINE-1 insertions are often associated with 3′ transduction of adjacent genomic sequences. Thus, the likely explanation for the mutagenic insertion is a LINE-1-mediated 3′ transduction with severe 5′ truncation. This is the first example of LINE-1-induced human disease caused by an “orphan” 3′ transduction.This work was carried out with the help of the Genetic Resources Core Facility (GRCF) at the Johns Hopkins University. LRE4 was found to be present in one Japanese individual out of 15 unrelated individuals in a LINE-1 targeted resequencing dataset. This dataset was generated by Illumina sequencing of the human-specific subfamily of LINE-1s (Ewing and Kazazian, 2010), using the service offered by the GRCF High Throughput Sequencing Center. Sequencing of the PCR products from the patient, as well as the cloned LRE4 sequence was done by the GRCF DNA Analysis Facility.
机译：长的Intersperseded Element-1（LINE-1）逆转座子占人类基因组的17％，并通过潜在的诱变“复制和粘贴”机制通过RNA中间体移动。最近，在日本男性中，逆转录转座介导的新转录本的插入被描述为遗传疾病的新病因，杜氏肌营养不良症。假定插入的序列来源于从chr转录的单拷贝非编码RNA。 11q22.3逆转录成chr的dystrophin基因。 X.在这里，我们证明了非参考全长LINE-1（称为LRE4）位于先证者和母体基因组的11q22.3号染色体上，直接位于序列的上游，其副本已插入到dystrophin基因中。 LRE4在细胞培养测定中具有很高的活性。 LINE-1插入通常与相邻基因组序列的3'转导相关。因此，诱变插入的可能解释是具有严重5'截短的LINE-1介导的3'转导。这是由“孤儿” 3'转导引起的LINE-1诱发人类疾病的第一个例子。这项工作是在约翰·霍普金斯大学的遗传资源核心基金（GRCF）的帮助下进行的。 LRE4被发现存在于LINE-1靶向重测序数据集中的15名无关个体中的一名日本个体中。该数据集是使用GRCF高通量测序中心提供的服务，通过对LINE-1s的人类特异性亚家族进行Illumina测序而生成的（Ewing和Kazazian，2010年）。通过GRCF DNA分析工具对患者的PCR产物以及克隆的LRE4序列进行测序。

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